npj Genomic Medicine (Sep 2021)
Contribution of rare variant associations to neurodegenerative disease presentation
- Allison A. Dilliott,
- Abdalla Abdelhady,
- Kelly M. Sunderland,
- Sali M. K. Farhan,
- Agessandro Abrahao,
- Malcolm A. Binns,
- Sandra E. Black,
- Michael Borrie,
- Leanne K. Casaubon,
- Dar Dowlatshahi,
- Elizabeth Finger,
- Corinne E. Fischer,
- Andrew Frank,
- Morris Freedman,
- David Grimes,
- Ayman Hassan,
- Mandar Jog,
- Sanjeev Kumar,
- Donna Kwan,
- Anthony E. Lang,
- Jennifer Mandzia,
- Mario Masellis,
- Adam D. McIntyre,
- Stephen H. Pasternak,
- Bruce G. Pollock,
- Tarek K. Rajji,
- Ekaterina Rogaeva,
- Demetrios J. Sahlas,
- Gustavo Saposnik,
- Christine Sato,
- Dallas Seitz,
- Christen Shoesmith,
- Thomas D. L. Steeves,
- Richard H. Swartz,
- Brian Tan,
- David F. Tang-Wai,
- Maria C. Tartaglia,
- John Turnbull,
- Lorne Zinman,
- ONDRI Investigators,
- Robert A. Hegele
Affiliations
- Allison A. Dilliott
- Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University
- Abdalla Abdelhady
- Department of Biology, Schulich School of Medicine and Dentistry, Western University
- Kelly M. Sunderland
- Rotman Research Institute, Baycrest Health Sciences
- Sali M. K. Farhan
- Departments of Neurology and Neurosurgery, and Human Genetics, Montreal Neurological Institute, McGill University
- Agessandro Abrahao
- Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre and University of Toronto
- Malcolm A. Binns
- Rotman Research Institute, Baycrest Health Sciences
- Sandra E. Black
- Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre and University of Toronto
- Michael Borrie
- St. Joseph’s Health Care Centre
- Leanne K. Casaubon
- Department of Medicine, Division of Neurology, University of Toronto
- Dar Dowlatshahi
- Department of Medicine, University of Ottawa
- Elizabeth Finger
- Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, Western University
- Corinne E. Fischer
- Keenan Research Centre for Biomedical Research, Li Ka Shing Knowledge Institute, St. Michael’s Hospital
- Andrew Frank
- Department of Medicine, University of Ottawa
- Morris Freedman
- Rotman Research Institute, Baycrest Health Sciences
- David Grimes
- Department of Medicine, University of Ottawa
- Ayman Hassan
- Thunder Bay Regional Research Institute and Northern Ontario School of Medicine
- Mandar Jog
- Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, Western University
- Sanjeev Kumar
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health
- Donna Kwan
- Centre for Neuroscience Studies, Queen’s University
- Anthony E. Lang
- Department of Medicine, Division of Neurology, University of Toronto
- Jennifer Mandzia
- Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, Western University
- Mario Masellis
- Department of Medicine, Division of Neurology, University of Toronto
- Adam D. McIntyre
- Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University
- Stephen H. Pasternak
- Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University
- Bruce G. Pollock
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health
- Tarek K. Rajji
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health
- Ekaterina Rogaeva
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto
- Demetrios J. Sahlas
- Department of Medicine, McMaster University
- Gustavo Saposnik
- Li Ka Shing Knowledge Institute, St. Michael’s Hospital
- Christine Sato
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto
- Dallas Seitz
- Cumming School of Medicine, University of Calgary
- Christen Shoesmith
- London Health Sciences Centre
- Thomas D. L. Steeves
- Department of Medicine, Division of Neurology, University of Toronto
- Richard H. Swartz
- Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre and University of Toronto
- Brian Tan
- Rotman Research Institute, Baycrest Health Sciences
- David F. Tang-Wai
- Department of Medicine, Division of Neurology, University of Toronto
- Maria C. Tartaglia
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto
- John Turnbull
- Department of Medicine, McMaster University
- Lorne Zinman
- Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre and University of Toronto
- ONDRI Investigators
- Robert A. Hegele
- Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University
- DOI
- https://doi.org/10.1038/s41525-021-00243-3
- Journal volume & issue
-
Vol. 6,
no. 1
pp. 1 – 9
Abstract
Abstract Genetic factors contribute to neurodegenerative diseases, with high heritability estimates across diagnoses; however, a large portion of the genetic influence remains poorly understood. Many previous studies have attempted to fill the gaps by performing linkage analyses and association studies in individual disease cohorts, but have failed to consider the clinical and pathological overlap observed across neurodegenerative diseases and the potential for genetic overlap between the phenotypes. Here, we leveraged rare variant association analyses (RVAAs) to elucidate the genetic overlap among multiple neurodegenerative diagnoses, including Alzheimer’s disease, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), mild cognitive impairment, and Parkinson’s disease (PD), as well as cerebrovascular disease, using the data generated with a custom-designed neurodegenerative disease gene panel in the Ontario Neurodegenerative Disease Research Initiative (ONDRI). As expected, only ~3% of ONDRI participants harboured a monogenic variant likely driving their disease presentation. Yet, when genes were binned based on previous disease associations, we observed an enrichment of putative loss of function variants in PD genes across all ONDRI cohorts. Further, individual gene-based RVAA identified significant enrichment of rare, nonsynonymous variants in PARK2 in the FTD cohort, and in NOTCH3 in the PD cohort. The results indicate that there may be greater heterogeneity in the genetic factors contributing to neurodegeneration than previously appreciated. Although the mechanisms by which these genes contribute to disease presentation must be further explored, we hypothesize they may be a result of rare variants of moderate phenotypic effect contributing to overlapping pathology and clinical features observed across neurodegenerative diagnoses.